Some piperazine derivatives having pharmaceutical activities such as Tachykinin antagonism have been known as described in EP 0655442 A1.
DISCLOSURE OF INVENTION
The object compound of the present invention can be represented by the following general formula (I): ##STR2## wherein Y is bond or lower alkylene,
R.sup.1 is aryl which may have suitable substituent(s), PA1 R.sup.2 is aryl or indolyl each of which may have suitable substituent(s), PA1 R.sup.3 is hydrogen or lower alkyl, PA1 R.sup.4 is chloro(lower)alkenyl; PA1 N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino; triazolylamino; morpholinoamino; lower alkoxy(lower)alkylamino; bis[(lower)alkoxy(lower)alkyl]amino; N-(lower alkyl)-N-[(lower)alkoxy(lower)alkyl]amino; imidazolyl; pyrazolyl; or 1,2,3,6-tetrahydropyridyl, 1,2,3,4-tetrahydroisoquinolyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl or saturated heterocyclic, each of which may have suitable substituent(s), PA1 saturated 3 to 8-membered (more preferably 5 to 7-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, hexamethyleneimino, etc.; PA1 saturated 3 to 8-membered (more preferably 5 to 6-membered) heteromonocyclic group containing 1 or 2 oxygen morpholinyl, sydnonyl, etc.; PA1 saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, thiomorpholinyl, etc.; PA1 saturated heterobicyclic group of the formula: ##STR10## (wherein l, m and n are each integer of 1 to 6); saturated heterobicyclic group of the formula: ##STR11## (wherein q, r, s and t are each integer of 1 to 6); and the like. PA1 Y is lower alkylene (more preferably C.sub.1 -C.sub.4 alkylene, most preferably methylene); PA1 R.sup.1 is aryl (more preferably C.sub.6 -C.sub.10 aryl, most preferably phenyl) which may have 1 to 3 (more preferably 1 or 2, most preferably 2) suitable substituent(s) [more preferably mono(or di or tri)halo(lower)alkyl (more preferably trihalo(lower)alkyl, most preferably trifluoromethyl)]; PA1 R.sup.2 is aryl (more preferably C.sub.6 -C.sub.10 aryl, most preferably phenyl or naphthyl) or indolyl each of which may have 1 to 3 (more preferably 1 or 2, most preferably 2) suitable substituent(s) [more preferably substituent selected from the group consisting of lower alkyl (more preferably C.sub.1 -C.sub.4 alkyl, most preferably methyl), lower alkoxy (more preferably C.sub.1 -C.sub.4 alkoxy, most preferably methoxy), mono(or di or tri)halo(lower)alkyl (more preferably mono(or di or tri)halo(C.sub.1 -C.sub.4)alkyl, most preferably trifluoromethyl) and halogen (more preferably chlorine or fluorine)]; PA1 R.sup.3 is hydrogen; and PA1 R.sup.4 is chloro(lower)alkenyl (more preferably chloro(C.sub.2 -C.sub.4)alkenyl, most preferably 4-chloro-2-butenyl); chloro(lower)alkynyl (more preferably chloro(C.sub.2 -C.sub.4)alkynyl, most preferably 4-chloro-2-butynyl; pyridyl(lower)alkylamino(lower)alkyl [more preferably pyridyl(C.sub.1 -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkyl, most preferably 2-[(3-pyridylmethyl)amino]ethyl, 2-[(4-pyridylmethyl)amino]ethyl or 3-[(3-pyridylmethyl)amino]propyl]; pyridyl(lower)alkylamino(lower)alkenyl (more preferably pyridyl(C.sub.1 -C.sub.4)alkylamino(C.sub.2 -C.sub.4)alkenyl, most preferably 4-[(3-pyridylmethyl)amino]-2-butenyl); N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino(lower)alkyl (more preferably N-(C.sub.1 -C.sub.4 alkyl)-N-[pyridyl(C.sub.1 -C.sub.4)alkyl]amino(C.sub.1 -C.sub.4)alkyl, more preferably 2-[N-methyl-N-(3-pyridylmethyl) amino]ethyl]; triazolylamino(lower)alkyl (more preferably triazolylamino(C.sub.1 -C.sub.4)alkyl, most preferably 3-(1,2,4-triazol-3-ylamino) propyl); lower alkoxy(lower)alkylamino(lower)alkyl (more preferably C.sub.1 -C.sub.4 alkoxy(C.sub.1 -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkyl, most preferably 2-(2-methoxyethyl)aminoethyl); bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl [more preferably bis[(C.sub.1 -C.sub.4)alkoxy(C.sub.1 -C.sub.4)alkyl]amino(C.sub.1 -C.sub.4)alkyl, alkyl, most preferably 3-[bis(2-methoxyethyl)amino]propyl]; N-(lower alkyl)-N-[(lower)alkoxy(lower)alkyl]amino(lower) alkyl [more preferably N-(C.sub.1 -C.sub.4 alkyl)-N-[(C.sub.1 -C.sub.4)alkoxy(C.sub.1 -C.sub.4)alkyl]amino(C.sub.1 -C.sub.4)alkyl, most preferably 2-[N-methyl-N-(2-methoxyethyl)amino]ethyl]; hydroxy(lower)alkyl (more preferably hydroxy(C.sub.1 -C.sub.4) alkyl, most preferably hydroxypropyl); lower alkylsulfonyloxy(lower)alkyl (more preferably C.sub.1 -C.sub.4 alkylsulfonyloxy(C.sub.1 -C.sub.4)alkyl, most preferably methylsulfonyloxypropyl); phenyl(lower)alkyl (more preferably phenyl(C.sub.1 -C.sub.4)alkyl, most preferably benzyl) which may have lower alkanoyl (more preferably C.sub.1 -C.sub.4 alkanoyl, most preferably acetyl), amino, lower alkanoylamino (more preferably C.sub.1 -C.sub.4 alkanoylamino, most preferably acetylamino), di(lower)alkylaminocarbonyl (more preferably di(C.sub.1 -C.sub.4)alkylaminocarbonyl, most preferably diethylaminocarbonyl) or nitro; lower alkoxyphenyl(lower)alkylcarbonyl (more preferably C.sub.1 -C.sub.4 alkoxyphenyl(C.sub.1 -C.sub.4)alkylcarbonyl, most preferably methoxyphenylmethylcarbonyl); lower alkanoylbenzoyl (more preferably C.sub.1 -C.sub.4 alkanoylbenzoyl, most preferably acetylbenzoyl); benzoyl(lower)alkyl (more preferably benzoyl(C.sub.1 -C.sub.4)alkyl, most preferably benzoylmethyl) which has lower alkyl (more preferably C.sub.1 -C.sub.4 alkyl, most preferably methyl), chlorine or di(lower)alkylamino (more preferably di(C.sub.1 -C.sub.4)alkylamino, most preferably dimethylamino); benzoyl(lower)alkyl (more preferably benzoyl(C.sub.1 -C.sub.4)alkyl, most preferably benzoylmethyl) which has halogen (more preferably fluorine) and lower alkyl (more preferably C.sub.1 -C.sub.4 alkyl, most preferably methyl); dihalobenzoyl(lower)alkyl [more preferably dihalobenzoyl(C.sub.1 -C.sub.4)alkyl, most preferably (difluorobenzoyl)methyl]; di(lower)alkylbenzoyl(lower)alkyl [more preferably di(C.sub.1 -C.sub.4)alkylbenzoyl(C.sub.1 -C.sub.4)alkyl, most preferably dimmethylbenzoylmethyl]; 3-fluorobenzoyl(lower)alkyl (more preferably 3-fluorobenzoyl (C.sub.1 -C.sub.4)alkyl, most preferably 3-fluorobenzoylmethyl); 3-(4-fluorobenzoyl)propyl; 4,4-ethylenedioxy-4-(4-fluorophenyl)butyl; piperazinylcarbonyl(lower)alkyl (more preferably piperazinylcarbonyl(C.sub.1 -C.sub.4)alkyl, most preferably piperazinylcarbonylmethyl) which has cyclopentyl or halophenyl (more preferably fluorophenyl); (2-pyridyl)(lower)alkyl (more preferably (2-pyridyl) (C.sub.1 -C.sub.4)alkyl, most preferably (2-pyridyl)methyl); (3-pyridyl)propyl (more preferably 3-(3-pyridyl)propyl); (3-pyridyl)(lower)alkynyl (more preferably 3-pyridyl) (C.sub.2 -C.sub.4)alkynyl, most preferably 3-(3-pyridyl)-2-propynyl); imidazolyl(lower)alkyl (more preferably imidazolyl(C.sub.1 -C.sub.4) alkyl, most preferably (1H-imidazol-1-yl)methyl, (1H-imidazol-2-yl)methyl or (1H-imidazol-4-yl)methyl) which may have lower alkyl (more preferably C.sub.1 -C.sub.4 alkyl, most preferably methyl); pyrazolyl(lower)alkyl (more preferably pyrazolyl(C.sub.1 -C.sub.4)alkyl, most preferably (1H-pyrazol-4-yl)methyl or 3-(1H-pyrazol-4-yl) propyl) which may have lower alkyl (more preferably C.sub.1 -C.sub.4 alkyl, most preferably methyl); thiomorpholinylcarbonyl(lower)alkyl (more preferably thiomorpholinylcarbonyl(C.sub.1 -C.sub.4)alkyl, most preferably thiomorpholinylcarbonylmethyl); (3-azabicyclo[3.2.2]non-3-yl)carbonyl(lower)alkyl (more preferably (3-azabicyclo[3.2.2]non-3-yl)carbonyl(C.sub.1 -C.sub.4) alkyl, most preferably (3-azabicyclo[3.2.2]non-3-yl) carbonylmethyl); or thienylcarbonyl(lower)alkyl (more preferably thienylcarbonyl(C.sub.1 -C.sub.4)alkyl, most preferably thienylcarbonylmethyl, 1,2,3,6-tetrahydropyridyl(lower) alkyl (more preferably 1,2,3,6-tetrahydropyridyl(C.sub.1 -C.sub.4) alkyl, most preferably 3-(1,2,3,6-tetrahydropyridin-1-yl) propyl), 1,2,3,6-tetrahydropyridyl(lower)alkynyl (more preferably 1,2,3,6-tetrahydropyridyl(C.sub.2 -C.sub.4)alkynyl, most preferably 4-(1,2,3,6-tetrahydropyridin-1-yl)-2-butynyl), 1,2,3,4-tetrahydroisoquinolyl(lower)alkyl (more preferably 1,2,3,4-tetrahydroisoquinolyl(C.sub.1 -C.sub.4)alkyl, most preferably 1,2,3,4-tetrahydroisoquinolylpropyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower)alkyl (more preferably 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl (C.sub.1 -C.sub.4)alkyl, most preferably 4,5,6,7-tetrahydrothieno[3,2-c]pyridinylpropyl), saturated heterocyclic(lower)alkyl (more preferably saturated heterocyclic(C.sub.1 -C.sub.4)alkyl, more preferably saturated heterocyclicethyl or saturated heterocyclicpropyl, most preferably saturated heterocyclicpropyl), saturated heterocyclic(lower)alkenyl (more preferably saturated heterocyclic(C.sub.2 -C.sub.4)alkenyl, most preferably saturated heterocyclicbutenyl), saturated heterocyclic(lower)alkynyl (more preferably saturated heterocyclic(C.sub.2 -C.sub.5)alkynyl, most preferably saturated heterocyclicbutynyl or saturated heterocyclicpentynyl), saturated heterocyclicamino(lower)alkyl (more preferably saturated heterocyclicamino(C.sub.1 -C.sub.4)alkyl, most preferably saturated heterocyclicaminopropyl), saturated heterocyclicamino(lower)alkenyl (more preferably saturated heterocyclicamino(C.sub.2 -C.sub.4)alkenyl, most preferably saturated heterocyclicaminobutenyl) or saturated heterocyclicamino(lower)alkynyl (more preferably saturated heterocyclicamino(C.sub.2 -C.sub.5)alkynyl, most preferably saturated heterocyclicaminobutynyl) [wherein "saturated heterocyclic moiety" is saturated 3 to 8-membered (more preferably 5 to 7-membered) heteromonocyclic group containing 1 to 4 (more preferably 1 or 2) nitrogen atom(s) (more preferably pyrrolidinyl, piperidyl, piperazinyl or hexamethyleneimino, most preferably piperidyl); saturated 3 to 8-membered (more preferably 5 to 7-membered) heteromonocyclic group containing 1 or 2 (more preferably 1) oxygen atom(s) and 1 to 3 (more preferably 1) nitrogen atom(s) (more preferably morpholinyl or homomorpholinyl, most preferably morpholinyl); saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 (more preferably 1) sulfur atom(s) and 1 to 3 (more preferably 1) nitrogen atom(s) (more preferably thiomorpholinyl); or saturated heterocyclic group of the formula: ##STR13## (more preferably 3-azabicyclo[3.2.2]non-3-yl)], each of which may have 1 to 3 (more preferably 1 or 2) suitable substituent(s) [more preferably substituent selected from the group consisting of cyclo(lower)alkyl (more preferably cyclohexyl), lower alkanoyl (more preferably C.sub.1 -C.sub.4 alkanoyl, most preferably acetyl), lower alkyl (more preferably C.sub.1 -C.sub.4 alkyl, most preferably methyl), mono (or di or tri)halo(lower)alkyl (more preferably monohalo(C.sub.1 -C.sub.4)alkyl, most preferably fluoromethyl), lower alkoxy (more preferably C.sub.1 -C.sub.4 alkoxy, most preferably methoxy), lower alkoxy(lower)alkyl (more preferably C.sub.1 -C.sub.4 alkoxy(C.sub.1 -C.sub.4)alkyl, most preferably methoxymethyl), halogen (more preferably chlorine), aryl (more preferably phenyl), cyano, oxo and bivalent group of the formula: ##STR14##
chloro(lower)alkenyl; pyridyl(lower)alkylamino(lower)alkyl; pyridyl(lower)alkylamino(lower)alkenyl; N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino(lower)alkyl; triazolylamino(lower)alkyl; lower alkoxy(lower)alkylamino(lower)alkyl; bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl; N-(lower alkyl)-N-[(lower)alkoxy(lower)alkyl]amino(lower) alkyl; hydroxy(lower)alkyl; lower alkylsulfonyloxy(lower)alkyl; phenyl(lower)alkyl which may have lower alkanoyl, amino, lower alkanoylamino, di(lower)alkylaminocarbonyl or nitro; lower alkoxyphenyl (lower)alkylcarbonyl; lower alkanoylbenzoyl; benzoyl(lower)alkyl which has lower alkyl, chlorine or di(lower)alkylamino; benzoyl(lower)alkyl which has halogen and lower alkyl; dihalobenzoyl(lower)alkyl; di(lower)alkylbenzoyl(lower)alkyl; 3-fluorobenzoyl(lower)alkyl; 3-(4-fluorobenzoyl)propyl; 4,4-ethylenedioxy-4-(4-fluorophenyl)butyl; piperazinylcarbonyl(lower)alkyl which has cyclopentyl or halophenyl; (2-pyridyl) (lower)alkyl; (3-pyridyl)propyl; (3-pyridyl) (lower)alkynyl; imidazolyl(lower)alkyl which may have lower alkyl; pyrazolyl(lower)alkyl which may have lower alkyl; thiomorpholinylcarbonyl(lower)alkyl; (3-azabicyclo[3.2.2]non-3-yl)carbonyl(lower)alkyl; or thienylcarbonyl(lower)alkyl, 1,2,3,6-tetrahydropyridyl(lower)alkyl, 1,2,3,6-tetrahydropyridyl(lower)alkynyl, 1,2,3,4-tetrahydroisoquinolyl(lower)alkyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower)alkyl, saturated heterocyclic(lower)alkyl, saturated heterocyclic(lower)alkenyl, saturated heterocyclic(lower)alkynyl, saturated heterocyclicamino(lower)alkyl, saturated heterocyclicamino(lower)alkenyl or saturated heterocyclicamino(lower)alkynyl, each of which may have suitable substituent(s),
and a pharmaceutically acceptable salt thereof.
It is to be noted that the object compound (I) may include one or more stereoisomers due to asymmetric carbon atom(s) and double bond, and all of such isomers and a mixture thereof are included within the scope of the present invention.
It is further to be noted that isomerization or rearrangement of the object compound (I) may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention.
It is also to be noted that the solvating form of the compound (I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I) are included within the scope of the present invention.
According to the present invention, the object compound (I) or a salt thereof can be prepared by processes which are illustrated in the following schemes.